A feedback regulatory loop between HIF-1α and miR-21 in response to hypoxia in cardiomyocytes

Yang Liu; Honggang Nie; Kuikui Zhang; Dan Ma; Guang Yang; Zhilei Zheng; Kai Liu; Bo Yu; Changlin Zhai; Shuang Yang

doi:10.1016/j.febslet.2014.05.067

A feedback regulatory loop between HIF-1α and miR-21 in response to hypoxia in cardiomyocytes

FEBS Lett. 2014 Aug 25;588(17):3137-46. doi: 10.1016/j.febslet.2014.05.067. Epub 2014 Jun 28.

Authors

Yang Liu¹, Honggang Nie¹, Kuikui Zhang², Dan Ma¹, Guang Yang³, Zhilei Zheng³, Kai Liu¹, Bo Yu¹, Changlin Zhai⁴, Shuang Yang⁵

Affiliations

¹ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China.
² Department of Cardiology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150086, China.
³ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
⁴ Department of Cardiology, The First Affiliated Hospital of Jiaxing University, Jiaxing 314000, China. Electronic address: yesterdaygun@126.com.
⁵ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, China. Electronic address: yangshuang0101_a@163.com.

PMID: 24983504
DOI: 10.1016/j.febslet.2014.05.067

Abstract

Accumulating evidence suggests that hypoxia-inducible factor 1α (HIF-1α) regulates numerous miRNAs and is crucial for cellular response to hypoxia. However, the relationship between HIF-1α and miR-21 in hypoxic cardiomyocytes is little known. We found that hypoxia induced HIF-1α and miR-21 expression. HIF-1α knockdown increased cell apoptosis and reduced miR-21 expression. Furthermore, we found that HIF-1α transcriptionally enhanced miR-21 promoter activity by binding to its promoter, which required the recruitment of CBP/p300. In addition, we found that miR-21 inhibition increased cell apoptosis and reduced HIF-1α expression, and modulated the PTEN/Akt pathway. Our results indicate that HIF-1α-miR-21 feedback contributes to the adaptation of cardiomyocytes to hypoxia, and has potential as therapeutic target for myocardial ischemia.

Keywords: Cardiomyocytes; Hypoxia; Hypoxia-inducible factor 1α (HIF-1α); MicroRNA; miR-21.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Hypoxia / drug effects
Cell Line
Cobalt / pharmacology
Feedback, Physiological* / drug effects
Gene Expression Regulation / drug effects
Gene Silencing
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Mice
MicroRNAs / genetics*
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism*
PTEN Phosphohydrolase / metabolism
Phosphorylation / drug effects
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Transcription, Genetic / drug effects
p300-CBP Transcription Factors / metabolism

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
MIRN21 microRNA, human
MIRN21 microRNA, mouse
MicroRNAs
Proto-Oncogene Proteins c-bcl-2
Cobalt
p300-CBP Transcription Factors
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
cobaltous chloride